GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation

Cell. 2007 Jun 1;129(5):983-97. doi: 10.1016/j.cell.2007.03.045.


In cells undergoing apoptosis, mitochondrial outer-membrane permeabilization (MOMP) is followed by caspase activation promoted by released cytochrome c. Although caspases mediate the apoptotic phenotype, caspase inhibition is generally not sufficient for survival following MOMP; instead cells undergo a "caspase-independent cell death" (CICD). Thus, MOMP may represent a point of commitment to cell death. Here, we identify glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a critical regulator of CICD. GAPDH-expressing cells preserved their clonogenic potential following MOMP, provided that caspase activation was blocked. GAPDH-mediated protection of cells from CICD involved an elevation in glycolysis and a nuclear function that correlated with and was replaced by an increase in Atg12 expression. Consistent with this, protection from CICD reflected an increase in and a dependence upon autophagy, associated with a transient decrease in mitochondrial mass. Therefore, GAPDH mediates an elevation in glycolysis and enhanced autophagy that cooperate to protect cells from CICD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Autophagy*
  • Caspases / metabolism
  • Cell Survival / physiology*
  • Cytochromes c / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenases / genetics
  • Glyceraldehyde-3-Phosphate Dehydrogenases / physiology*
  • HeLa Cells
  • Humans
  • Jurkat Cells
  • Mitochondria / metabolism
  • Mitochondrial Membranes / metabolism
  • RNA Interference


  • Cytochromes c
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Caspases